Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila

The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene <i>Drp1</i> in <i>Drosophila melanogaster</i> and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and <i>Drp1</i> mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the <i>Dopa decarboxylase-Gal4</i> (<i>Ddc-Gal4</i>) transgene was exploited to direct the expression of <i>Drp1</i> and <i>Drp1-RNAi</i> transgenes in select neurons. Here, the knockdown of <i>Drp1</i> seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of <i>Buffy</i> suppresses the poor climbing induced by the knockdown of the <i>Drp1</i> function. The consequences of <i>Drp1</i> overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival <i>Bcl-2</i> gene <i>Buffy</i> or by the co-knockdown of the pro-cell death <i>Bcl-2</i> homologue <i>Debcl</i>. Alteration of the expression of <i>Drp1</i> acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of <i>Buffy</i> can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of <i>Drp1</i> or the RNA interference of <i>Drp1</i> has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.